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Abstract: Secondary degeneration leads to an expansion of the initial tissue damage sustained during a spinal cord injury (SCI). Dampening the cellular inflammatory response that contributes to this progressive tissue damage is one possible strategy for neuroprotection after acute SCI. We initially examined whether treatment with a PEGylated form of rat interferon-beta (IFN-β) would modulate the expression of several markers of inflammation and neuroprotection at the site of a unilateral cervical level 5 contusion injury. Adult female Sprague–Dawley rats were injured using the Infinite Horizon Impactor at a force of 200 kdyn (equivalent to a severe injury) and a mean displacement of 1600–1800 μm. A single dose (5×106 units) of PEGylated IFN-β or vehicle was administered 30 min following SCI. Here we demonstrate temporal changes in pro- and anti-inflammatory cytokine levels and the expression of heat shock proteins and iNOS (involved in neuroprotection) at the lesion epicenter and one segment caudally after SCI and PEG IFN-β treatment. The results suggested a potential therapeutic treatment strategy for modulation of secondary damage after acute SCI. Therefore, we examined whether acute treatment with PEG IFN-β would improve forelimb function alone or when combined with forced exercise (Ex). Animals began the Ex paradigm 5 days post SCI and continued for 5 days/week over 8 weeks. Locomotion (forelimb locomotor scale [FLS], hindlimb BBB, and TreadScan) and sensorimotor function (grid walking) was tested weekly. Additional outcome measures included lesion size and glial cell reactivity. Significant FLS improvements occurred at 1 week post SCI in the PEGylated IFN-β-treated group but not at any other time point or with any other treatment approaches. These results suggest that this acute neuroprotective treatment strategy does not translate into long term behavioral recovery even when combined with forced exercise. [Copyright &y& Elsevier]

Abstract: We investigated microRNAs (miRs) associated with PTEN/mTOR signaling after spinal cord injury (SCI) and after hind limb exercise (Ex), a therapy implicated in promoting spinal cord plasticity. After spinalization, rats received cycling Ex 5days/week. The expression of miRs, their target genes and downstream effectors were probed in spinal cord tissue at 10 and 31days post injury. Ex elevated expression of miR21 and decreased expression of miR 199a-3p correlating with significant change in the expression of their respective target genes: PTEN mRNA decreased and mTOR mRNA increased. Western blotting confirmed comparable changes in protein levels. An increase in phosphorylated-S6 (a downstream effector of mTOR) within intermediate grey neurons in Ex rats was blocked by Rapamycin treatment. It thus appears possible that activity-dependent plasticity in the injured spinal cord is modulated in part through miRs that regulate PTEN and mTOR signaling and may indicate an increase in the regenerative potential of neurons affected by a SCI. [Copyright &y& Elsevier]

Abstract: Peripheral nerve grafts (PNG) into the rat spinal cord support axon regeneration after acute or chronic injury, with synaptic reconnection across the lesion site and some level of behavioral recovery. Here, we grafted a peripheral nerve into the injured spinal cord of cats as a preclinical treatment approach to promote regeneration for eventual translational use. Adult female cats received a partial hemisection lesion at the cervical level (C7) and immediate apposition of an autologous tibial nerve segment to the lesion site. Five weeks later, a dorsal quadrant lesion was performed caudally (T1), the lesion site treated with chondroitinase ABC 2 days later to digest growth inhibiting extracellular matrix molecules, and the distal end of the PNG apposed to the injury site. After 4–20weeks, the grafts survived in 10/12 animals with several thousand myelinated axons present in each graft. The distal end of 9/10 grafts was well apposed to the spinal cord and numerous axons extended beyond the lesion site. Intraspinal stimulation evoked compound action potentials in the graft with an appropriate latency illustrating normal axonal conduction of the regenerated axons. Although stimulation of the PNG failed to elicit responses in the spinal cord distal to the lesion site, the presence of c-Fos immunoreactive neurons close to the distal apposition site indicates that regenerated axons formed functional synapses with host neurons. This study demonstrates the successful application of a nerve grafting approach to promote regeneration after spinal cord injury in a non-rodent, large animal model. [ABSTRACT FROM AUTHOR]